This project is to determine if synaptic adhesive proteins (SAPs), neuroligins and neurexins mediate the antidepressive effects of sleep-deprivation (SD) and drug treatments. Although some antidepressant drugs are effective treatments for depressive disorders, the efficacy of these treatments remains to be improved. Currently only one-third of patients with acute pure major depression achieve remission after the first-line antidepressant monotherapy. Up to two-thirds of patients with major depression do not respond to the first medication. More importantly, the beneficial effect of antidepressants usually does not occur within the few weeks of the treatment. This makes the treatment less tolerated during the first few weeks, and many patients discontinue treatment. However, SD improves mood immediately according to cumulative evidence in last 30 years of research without knowing the mechanisms and the difference for the effect between SD and antidepressant treatment. We hypothesize that restoration of normal prefrontal cortical synaptic excitability and the balance between neuroligins and neurexins plays a critical role in the reversal of depression symptoms by SD, orexins and SSRI treatment. We further hypothesize that the suppression of neuroligin 1 expression may eliminate the immediate antidepressive effect of SD and orexins and the antidepressive effect by chronic SSRI treatment. This proposed project will conduct studies in three specific aims. Aim 1 will determine the differential expression of SAPs in rodent models of depression. We have found that neuroligins and neurexins are altered differently in a rat model of depression induced by neonatal exposure to clomipramine. To further define the potential impact of SAPs in the pathology of depression and the regulation of antidepressive effects, we propose to examine SAPs in a rat model and mouse model of depression with different genetic background. Aim 2 will compare the alterations of SAPs in a rat model of depression among treatments with SD, orexins and fluoxetine. We will first compare the short-term effects of SD by gentle handling to that of SD by orexin and the acute effect of fluoxetine. Secondly, we will compare effects of long-term treatment with fluoxetine vs. orexin on behavior and SAPs. We will determine if SAPs, especially, neuroligins and neurexins are differentially regulated in depression models. Aim 3 will determine the effect of neuroligin 1 siRNA on SD, orexins and fluoxetine induced antidepressive effects. We will utilize neuroligin-1 siRNA to alter the expression of neuroligin 1 in the prefrontal cortex and to measure depressive behaviors and biomarkers of depressive pathology in the pre-frontal cortex in mice regarding the effects of manual SD and SD induced by orexins and fluoxetine treatment.